Title:Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases
Volume: 16
Issue: 2
Author(s): Ajmer Singh Grewal, Shashikant Bhardwaj, Deepti Pandita, Viney Lather and Bhupinder Singh Sekhon
Affiliation:
Keywords:
Aldose reductase, Aldose reductase inhibitors, Cataract, Diabetes, Nephropathy, Neuropathy, Polyol pathway,
Retinopathy, Sepsis complications.
Abstract: Diabetes mellitus occurrence has been associated to the modification of the physiological
levels of glucose and is often accompanied by several long-term complications, namely neuropathy,
nephropathy, retinopathy, cataract, and cardiovascular. Aldose reductase (AR) is an enzyme of aldoketo
reductase super-family that catalyzes the conversion of glucose to sorbitol in the polyol pathway
of glucose metabolism. In this context, aldose reductase inhibitors (ARIs) have received much attention worldwide.
Decreased sorbitol flux through polyol pathway by ARIs could be an emerging target for the management of major
complications of diabetes. The present review article describes a brief overview of the role of aldose reductase in the
diabetic complications, advances achieved on ARIs and their potential use in the treatment and management of the major
diabetic complications such as cataract, retinopathy, neuropathy, nephropathy and cardiovascular. The ARIs developed
vary structurally, and representative structural classes of ARIs include i) carboxylic acid derivatives (such as Epalrestat,
Alrestatin, Zopalrestat, Zenarestat, Ponalrestat, Lidorestat, and Tolrestat), ii) spirohydantoins and related cyclic amides
(such as Sorbinil, Minalrestat, and Fidarestat), and iii) phenolic derivatives (related to Benzopyran-4-one and Chalcone).
Among these inhibitors, Epalrestat is the only commercially available inhibitor till date. In addition, some other ARIs
such as Sorbinil and Ranirestat had been advanced into late stage of clinical trials and found to be safe for human use. The
role of various natural ARIs in management of diabetic complications will be discussed. Adapting ARIs could prevent
sepsis complications, prevent angiogenesis, ameliorate mild or asymptomatic diabetic cardiovascular autonomic
neuropathy and appear to be a promising strategy for the treatment of endotoxemia and other ROS-induced inflammatory
diseases. The role of ARIs in non-diabetic diseases will also be discussed.